Evaluation of computational chemistry methods: crystallographic and cheminformatics analysis of aminothiazole methoximes

Cheminformatics is used to validate the capabilities of widely used quantum chemistry and molecular mechanics methods. Among the quantum methods examined are the semiempirical MNDO, AM1, and PM3 methods, Hartree-Fock (ab initio) at a range of basis set levels, density functional theory (DFT) at a range of basis sets, and a post-Hartree-Fock method, local Moller-Plesset second-order perturbation theory (LMP2). Among the force fields compared are AMBER, MMFF94, MMFF94s, OPLS/A, OPLS-AA, Sybyl, and Tripos. Programs used are Spartan, MacroModel, SYBYL, and Jaguar. The test molecule is (2-amino-5-thiazolyl)-alpha-(methoxyimino)-N-methylacetamide, a model of the aminothiazole methoxime (ATMO) side chain of third-generation cephalosporin antibacterial agents. The Ward hierarchical clustering technique yields an insightful comparison of experimental (X-ray) and calculated (energy optimized) bond lengths and bond angles. The computational chemistry methods are also compared in terms of the potential energy curves they predict for internal rotation. Clustering analysis and regression analysis are compared. The MMFF94 force field such as implemented in MacroModel is the best overall computational chemistry method at reproducing crystallographic data and conformational properties of the ATMO moiety. This work demonstrates that going to a higher level of quantum theory does not necessarily give better results and that quantum mechanical results are not necessarily better than molecular mechanics results.     

Evaluation of ion mobility spectroscopy for determining charge-solvated versus salt-bridge structures of protonated trimers

The cross sections of five different protonated trimers consisting of two base molecules and trifluoroacetic acid were measured by using ion mobility spectrometry. The gas-phase basicities of these five base molecules span an 8-kcal/mol range. These cross sections are compared with those determined from candidate low-energy salt-bridge and charge-solvated structures identified by using molecular mechanics calculations using three different force fields: AMBER*, MMFF, and CHARMm. With AMBER*, the charge-solvated structures are all globular and the salt-bridge structures are all linear, whereas with CHARMm, these two forms of the protonated trimers can adopt either shape. Globular structures have smaller cross sections than linear structures. Conclusions about the structure of these protonated trimers are highly dependent on the force field used to generate low-energy candidate structures. With AMBER*, all of the trimers are consistent with salt-bridge structures, whereas with MMFF the measured cross sections are more consistent with charge-solvated structures, although the assignments are ambiguous for two of the protonated trimers. Conclusions based on structures generated by using CHARMm suggest a change in structure from charge-solvated to salt-bridge structures with increasing gas-phase basicity of the constituent bases, a result that is most consistent with structural conclusions based on blackbody infrared radiative dissociation experiments for these protonated trimers and theoretical calculations on the uncharged base-acid pairs.     

Electronic Structure and Circular Dichroism of Natural Alboatisins Isolated from Aerial Parts of Isodon Albopilosus: DFT and TDDFT Study

The stable conformations of a series of bioactive molecules, (?)-alboatisins A?C, are identified via Monte Carlo searching with the MMFF94 molecular mechanics force field. Then, the optical rotation (OR) values, vibrational circular dichroism (VCD), and electronic circular dichroism (ECD) spectra were calculated using the gradient-corrected density functional theory method. The vibrational and transition modes of molecular chirality were explored in terms of their microscopic origin. The calculated specific rotations are in agreement with the experimental values. From the OR analysis, it was concluded that optical rotation values areregulated by hydroxyl substitution. Vibrations occurring on the chiral skeleton may cause strong absorption in VCD spectra; VCD spectra are thus the spectral response to deformation vibrations on the chiral carbon skeleton. The lowest-energy negative Cotton effect is caused by σ→π^* transition. Frontier molecular orbital analysis showed that strong ECD absorptions are produced when the dominant transition on the chiral skeleton is asymmetric; ECD spectra show the result of transitions lacking asymmetry on the chiral skeleton.     

Computational structural determination and energy landscape analysis of the hepatic carcinogen 2-(acetylamino)fluorene

 2-(Acetylamino)fluorene (AAF), a potent mutagen and a prototypical example of the mutagenic aromatic amines, forms covalent adducts to DNA after metabolic activation in the liver. A benchmark study of AAF is presented using a number of the most widely used molecular mechanics and semiempirical computational methods and models. The results are compared to higher-level quantum calculations and to experimentally obtained crystal structures. Hydrogen bonding between AAF molecules in the crystal phase complicates the direct comparison of gas-phase theoretical calculations with experiment, so Hartree–Fock (HF) and Becke–Perdew (BP) density functional theory (DFT) calculations are used as benchmarks for the semiempirical and molecular mechanics results. Systematic conformer searches and dihedral energy landscapes were carried out for AAF using the SYBYL and MMFF94 molecular mechanics force fields; the AM1, PM3 and MNDO semiempirical quantum mechanics methods; HF using the 3-21G*and 6-31G* basis sets; and DFT using the nonlocal BP functional and double numerical polarization basis sets. MMFF94, AM1, HF and DFT calculations all predict the same planar structures, whereas SYBYL, MNDO and PM3 all predict various nonplanar geometries. The AM1 energy landscape is in substantial agreement with HF and DFT predictions; MMFF94 is qualitatively similar to HF and DFT; and the MNDO, PM3 and SYBYL results are qualitatively different from the HF and DFT results and from each other. These results are attributed to deficiencies in MNDO, PM3 and SYBYL. The MNDO, PM3 and SYBYL models may be unreliable for compounds in which an amide group is immediately adjacent to an aromatic ring. Received: 26 May 2002 / Accepted: 12 December 2002 / Published online: 14 February 2003     

Molecular mechanics conformational analysis of tylosin

The conformations of the 16-membered macrolide antibiotic tylosin were studied with molecular mechanics (AMBER* force field) including modelling of the effect of the solvent on the conformational preferences (GB/SA). A Monte Carlo conformational search procedure was used for finding the most probable low-energy conformations. The present study provides complementary data to recently reported analysis of the conformations of tylosin based on NMR techniques. A search for the low-energy conformations of protynolide, a 16-membered lactone containing the same aglycone as tylosin, was also carried out, and the results were compared with the observed conformation in the crystal as well as with the most probable conformations of the macrocyclic ring of tylosin. The dependence of the results on force field was also studied by utilizing the MM3 force field. Some particular conformations were computed with the semiempirical molecular orbital methods AM1 and PM3.     

Solution structure of folic acid. Molecular mechanics and NMR investigation

The structure of folic acid in solution was investigated by nuclear magnetic resonance (NMR) and theoretical calculations. Dynamical information and geometrical constraints were obtained by carbon-13 relaxation study, homo-nuclear NOESY spectra and hetero-nuclear 1H-13C NOE experiments. This set of experimental data was used for the molecular mechanics and molecular dynamic calculations. The accuracy of the final structure was established by the R(NMR) factor, which was calculated comparing the experimental NOESY cross-peaks intensities and the corresponding values simulated by using the complete relaxation matrix analysis (CORMA) approach.     

Conformational analysis of ochratoxin a by NMR spectroscopy and computational molecular modeling

Two-dimensional NMR spectroscopy has been used for a complete assignment of the proton and carbon-13 spectra of the metabolite from Aspergillus ochraceus, ochratoxin A. In addition, phase-sensitive nuclear Overhauser effect spectrometry experiments and computational molecular modeling (MM2 and MMFF force field programs) have been employed to examine the conformational properties of ochratoxin A in chloroform solutions. Particular attention has been given to intramolecular hydrogen-bonding formation involving the phenolic group on dihydroisocoumarin, which may be responsible for the toxic mechanism of ochratoxin A.     

Force-field and quantum-mechanical binding study of selected SAMPL3 host-guest complexes

A Merck molecular force field classical potential combined with Poisson-Boltzmann electrostatics (MMFF/PB) has been used to estimate the binding free energy of seven guest molecules (six tertiary amines and one primary amine) into a synthetic receptor (acyclic cucurbit[4]uril congener) and two benzimidazoles into cyclic cucurbit[7]uril (CB[7]) and cucurbit[8]uril (CB[8]) hosts. In addition, binding enthalpies for the benzimidazoles were calculated with density functional theory (DFT) using the B3LYP functional and a polarizable continuum model (PCM). Although in most cases the MMFF/PB approach returned reasonable agreements with the experiment (±2 kcal/mol), significant, much larger deviations were reported in the case of three host-guest pairs. All four binding enthalpy predictions with the DFT/PCM method suffered 70% or larger deviations from the calorimetry data. Results are discussed in terms of the molecular models used for guest-host complexation and the quality of the intermolecular potentials.     

Structures of protonated arginine dimer and bradykinin investigated by density functional theory: further support for stable gas-phase salt bridges

The gas-phase structures and energetics of both protonated arginine dimer and protonated bradykinin were investigated using a combination of molecular mechanics with conformational searching to identify candidate low-energy structures, and density functional theory for subsequent minimization and energy calculations. For protonated arginine dimer, a good correlation (R = 0.88) was obtained between the molecular mechanics and EDF1 6-31+G* energies, indicating that mechanics with MMFF is suitable for finding low-energy conformers. For this ion, the salt-bridge or ion-zwitterion form was found to be 5.7 and 7.2 kcal/mol more stable than the simple protonated or ion-molecule form at the EDF1 6-31++G** and B3LYP 6-311++G** levels. For bradykinin, the correlation between the molecular mechanics and DFT energies was poor (R = 0.28), indicating that many low-energy structures are likely passed over in the mechanics conformational searching. This result suggests that structures of this larger peptide ion obtained using mechanics calculations alone are not necessarily reliable. The lowest energy structure of the salt-bridge form of bradykinin is 10.6 kcal/mol lower in energy (EDF1) than the lowest energy simple protonated form at the 6-311G* level. Similarly, the average energy of all salt-bridge structures investigated is 13.6 kcal/mol lower than the average of all the protonated forms investigated. To the extent that a sufficient number of structures are investigated, these results provide some additional support for the salt-bridge form of bradykinin in the gas phase.     

Synthesis and physical properties of protein core mimetics.

A series of mimetic cores composed of a synthetic scaffold and amino acids have been constructed and their properties investigated in chloroform. A relative measure of H-bond strength was obtained by comparing temperature coefficients derived from variable-temperature (1)H NMR experiments. Although most templates had a strong H-bond, only a single template composed of D- and L-phenylalanines was able to form two strong H-bonds. Templates containing D- and L-leucines formed only a single H-bond. The results of these studies suggest that aromatic edge-to-face interactions provide greater stabilization energy than aliphatic-aromatic interactions in the tightly packed hydrophobic cores of proteins. Partial structures of the templates were derived by analyzing a series of two-dimensional (1)H NMR spectra and performing molecular mechanics calculations using AMBER and MMFF94 force fields.     

MMFF VI. MMFF94s option for energy minimization studies

This article describes the derivation of MMFF94s, which is the “s” (static) variant of MMFF94. MMFF94s incorporates altered out of plane bending parameters that yield planar (or nearly planar) energy-minimized geometries at unstrained delocalized trigonal nitrogen centers. Some experimental and most theoretical structures show appreciable puckering at nitrogen in isolated structures. However, condensed-phase effects or even strong intermolecular hydrogen bonding tends to reduce, but need not eliminate, such puckering; in contravention to results reported on the lower level Hartree–Fock surface, we show in the correlated LMP2/6-31G** calculations for the Watson–Crick guanine–cytosine base pair that one of the hydrogen-bonded NH₂ groups remains appreciably puckered. The resultant MMFF94s geometries emulate the “time-averaged” structures typically observed in crystallographic and most other experimental structure determinations. MMFF94s also employs modified torsion parameters for interactions that involve such centers, but is identical to MMFF94 for other systems. Isolated instances are found in which MMFF94s fails to locate a (probably shallow) local minimum found on the MMFF94 and reference MP2/6-31G* surfaces. In general, however, MMFF94s describes conformation energies for delocalized trigonal nitrogen systems nearly as well as MMFF94 does. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 720–729, 1999     

Atom equivalents for converting DFT energies calculated on molecular mechanics structures to formation enthalpies

New atom equivalents are introduced to convert BP/DN**//MMFF energies into formation enthalpies. As a result of using molecular mechanics structures, poor results are obtained for compounds outside the scope of the force field, such as those bearing  NF₂ groups or some nitrogenous systems. Notwithstanding these limitations, present procedures compare well with the results of previous atom equivalents schemes. Indeed, rms deviations from experiment are below 9 kJ/mol for hydrocarbons, and close to 16 kJ/mol for a variety of compounds reasonably well described by MMFF. The explicit inclusion of thermal and vibrational contributions, using calculated frequencies, does not improve the results. This study demonstrates that cost‐effective approaches to formation enthalpies may be developed on the basis of a combination of DFT with a suitable molecular mechanics force field. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 367–379, 2000     

ICFF: a new method to incorporate implicit flexibility into an internal coordinate force field

We introduce a new method to accurately "project" a Cartesian force field onto an internal coordinate molecular model with fixed-bond geometry. The algorithm automatically generates the Internal Coordinate Force Field (ICFF), which is a close approximation of the "source" Cartesian force field. The ICFF method reduces the number of free variables in a model by at least 10-fold and facilitates the fast convergence of geometry optimizations, an advantage that is critical for many applications such as the docking of flexible ligands or conformational modeling of macromolecules. Although covalent geometry is fixed in an ICFF model, implicit flexibility is incorporated into the force field parameters in the following two ways. First, we formulate an empirical torsion energy term in ICFF as a sixfold Fourier series and develop a procedure to calculate the Fourier coefficients from the conformational energy profiles of the fully flexible Cartesian model. The ICFF torsion parameters thus represent not only torsion component of the source force field, but also bond bending, bond stretching, and "1-4" van der Waals interactions. Second, we use a soft polynomial repulsion function for "1-5" and "1-6" interactions to mimic the flexibility of bonds, connecting these atoms. Also, we suggest a way to use a local part of the Cartesian force field to automatically generate fixed covalent geometries, compatible with the ICFF energy function. Here, we present an implementation of the ICFF algorithm, which employs the MMFF94s Cartesian force field as a "source." Extensive benchmarking of ICFF with a representative set of organic molecules demonstrates that the implicit flexibility model accurately reproduces MMFF94s equilibrium conformational energy differences (RMSD approximately 0.64 kcal) and, most importantly, detailed torsion energy profiles (RMSD approximately 0.37 kcal). This accuracy is characteristic of the method, because all the ICFF parameters (except one scaling factor in the "1-5,1-6" repulsion term) are derived directly from the source Cartesian force field and do not depend on any particular molecular set. In contrast, the rigid geometry model with the MMFF94s energy function yields highly biased estimations in this test with the RMSD exceeding 1.2 kcal for the equilibrium energy comparisons and approximately 3.4 kcal for the torsion energy profiles.     

DommiMOE: an implementation of ligand field molecular mechanics in the molecular operating environment

The ligand field molecular mechanics (LFMM) model, which incorporates the ligand field stabilization energy (LFSE) directly into the potential energy expression of molecular mechanics (MM), has been implemented in the "chemically aware" molecular operating environment (MOE) software package. The new program, christened DommiMOE, is derived from our original in-house code that has been linked to MOE via its applications programming interface and a number of other routines written in MOE's native scientific vector language (SVL). DommiMOE automates the assignment of atom types and their associated parameters and popular force fields available in MOE such as MMFF94, AMBER, and CHARMM can be easily extended to provide a transition metal simulation capability. Some of the unique features of the LFMM are illustrated using MMFF94 and some simple [MCl)]2- and [Ni(NH3)n]2+ species. These studies also demonstrate how density functional theory calculations, especially on experimentally inaccessible systems, provide important data for designing improved LFMM parameters. DommiMOE treats Jahn-Teller distortions automatically, and can compute the relative energies of different spin states for Ni(II) complexes using a single set of LFMM parameters.     

The Absolute Configuration of the Fungal Metabolite Verrucarin B. Biosynthetic Consequences. Verrucarins and roridins, 36th communication

The absolute configuration of verrucarin B (2) has been determined by a single crystal X-ray diffraction analysis. This result permits the stereochemistry of the biogenetic transformation of mevalonic acid (12) to verrucarinic acid (7) to be deduced.     

Starting point to molecular design: efficient automated 3D model builder Key3D

Obtaining three-dimensional (3D) structures from structural formulae is a crucial process in molecular design. We have developed a new 3D model builder, Key3D, in which the simplified distance geometry technique and structure optimization based on the MMFF force field are combined. In an evaluation study using 598 crystal structures, the high performance and accuracy of Key3D were demonstrated. In the "flexible-fitting" test, which is focused on practical usefulness in the molecular design process, 88% of the Key3D structures acceptably reproduced the reference crystal structures (root-mean-square deviation <0.6 A) upon rotation of acyclic bonds. These results indicate that Key3D will be very effective in providing starting points for practical molecular design.